Crinetics Pharmaceuticals - Earnings Call - Q2 2025

Executive Summary

• Q2 2025 revenue beat consensus while EPS missed: $1.03M vs $0.49M consensus (+$0.54M), EPS $(1.23) vs $(1.10) consensus; EBITDA was below consensus (actual $(128.2)M vs $(115.9)M). Management highlighted continued FDA engagement with a 9/25/2025 PDUFA for PALSONIFY (paltusotine) and reiterated commercial readiness.
• Cash, cash equivalents and investments were $1.20B, supporting runway into 2029; CFO narrowed FY25 net cash used in operations guidance to $340–$370M (from $340–$380M) and flagged a higher H2 burn as trials and commercialization ramp.
• Operating expenses rose sharply YoY as R&D and SG&A scaled for multiple late-stage programs and launch build-out, driving a wider net loss of $(115.6)M vs $(74.1)M YoY.
• Near-term stock catalysts: PDUFA decision (9/25), Phase 3 initiations (carcinoid syndrome, adult/pediatric CAH), and continued payer/formulary progress; management emphasized launch cadence will be gradual given visit frequency and payer timelines.

What Went Well and What Went Wrong

What Went Well

• Paltusotine NDA review “on track” with continued, productive FDA engagement; EMA MAA validated with potential EMA decision in H1 2026.
• Commercial build-out nearly complete; ~30 sales reps targeted; pre-approval payer discussions receptive to value proposition (faster disease control, lower burden, improved adherence).
• Strong cash balance of $1.20B and extended runway “into 2029,” enabling parallel execution across late-stage programs and launch prep.
  • Quote: “Overall, Crinetics is in the strongest position in its history, with unprecedented momentum… and a clear path toward delivering transformative therapies to patients.” — CEO Scott Struthers.
  • Quote: “We are more confident than ever in the long term potential for PALSONIFY to become the preferred treatment for the acromegaly community.” — CCO Isabel Kalofonos.

What Went Wrong

• EPS missed consensus (actual $(1.23) vs $(1.10)), and EBITDA underperformed estimates (actual $(128.2)M vs $(115.9)M), reflecting heavier spend into R&D and SG&A.
• Operating expenses surged YoY (R&D $80.3M vs $58.3M; SG&A $49.8M vs $24.8M) as clinical programs and commercial readiness scaled, widening net loss to $(115.6)M (vs $(74.1)M YoY).
• Launch pace expected to be gradual (patients see endos 2–4x/yr; formulary placement 6–9 months), tempering near-term revenue ramp clarity; distribution will be closed and data blocked from services like IQVIA, limiting external tracking at launch.

Transcript

Speaker 7

Welcome to Crinetics Pharmaceuticals' second quarter 2025 financial results conference call. At this time, all participants are in listen-only mode. Following the management's prepared remarks, we will hold a question and answer session. In order to raise a question, please signal by pressing star followed by one on your telephone keypad. To remove yourself from the line of questioning, please press star followed by two. I would like to turn the call over to Gayathri Diwakar, Head of Investor Relations. Please go ahead.

Speaker 5

Thank you, operator. Good afternoon, everyone, and thank you for joining us to discuss the second quarter 2025 results. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; Dr. Dana Pizzuti, Chief Medical and Development Officer; Isabel Kalofonos, Chief Commercial Officer; and Hrvi Sophie, Chief Financial Officer. In addition, Dr. Stephen F. Betz, Founder and Chief Scientific Officer, and Dr. Alan S. Krasner, Chief Endocrinologist, will also be joining for the Q&A portion. Please note there's a slide deck for today's presentation, which is in the Events and Presentations section of the Investors page on the Crinetics Pharmaceuticals website. In addition, a press release was issued earlier today and is also available on the corporate website. Slide two.

As a reminder, we'll be making forward-looking statements, and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filing. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's business. In particular, today we will be reviewing our commercialization plans as well as estimates related to market size, bills, and other data about the aforementioned market. Projections, assumptions, and estimates of a future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.

These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Crinetics Pharmaceuticals' SEC filings, including its annual report on Form 10-K, the quarterly report on Form 10-K. I would also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of live broadcast, August 7, 2025. Crinetics Pharmaceuticals takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. With that, I'll hand the call over to Scott.

Speaker 2

Thank you, Gayathri, and good afternoon to everyone joining today's call. Turning to slide three, we are pleased to provide an update on our corporate progress and share our second quarter results. We continue to execute on our mission to develop innovative therapies for patients with endocrine diseases and endocrine-related tumors. As we approach the pivotal moment of our pending approval of our first NDA, I'm pleased to report strong execution across all aspects of our business. I want to begin by reaffirming that the Pellicetti NDA review remains on track. We continue to work closely with the FDA towards an anticipated approval in September. We are grateful for the FDA's commitment to its important work and their collaborative approach throughout the process. Our regulatory team has maintained excellent momentum and remains confident in our timeline and preparations for what will be a transformational launch for Crinetics.

We've assembled an outstanding launch team of experienced professionals, both in our headquarters and in the field, who bring deep expertise in endocrinology and rare disease commercialization. The caliber of talent we've attracted speaks to the excitement around Pellicetti and its potential impact on patient care. Recently, we hosted a group of more than 40 people living with acromegaly at our headquarters in San Diego as part of our ongoing engagement with the patient community. We have worked with the Acromegaly Advocacy Group since before Pellicetti entered the clinic. We continue to seek their insights to shape our commercial strategy. At this most recent patient event, I heard directly about their experiences with their disease and their interactions with the healthcare systems around the country.

After talking with them personally, I am more confident than ever that Pellicetti's profile addresses a critical unmet need that will make a very positive impact on all these patients' daily lives. Deeper in the pipeline, we continue to make progress towards initiating four additional pivotal programs. Trials of Pellicetti for the treatment of carcinoid syndrome and ethumelonint for the treatment of adult and pediatric congenital adrenal hyperplasia are ramping up now. We remain highly encouraged by the potential of ethumelonint's novel mechanism of action in ACTH-dependent Cushing’s syndrome, and following extensive conversations with multiple regulatory authorities, anticipate initiation of a phase two-three study in the first half of 2026. The enthusiasm for our earlier pipeline continues to build. The phase one-two study of CRN9682 in SST2 expressing solid tumors is ramping up, and our work towards IND submissions across multiple additional discovery stage programs continues.

As you may have seen, we've been extremely active at several key endocrinology conferences over the last few months, including Endo 2025 last month in San Francisco. We delivered six poster presentations and two oral presentations covering Pellicetti and acromegaly, ethumelonint and CAH, and our thyroid stimulating hormone or TSH receptor antagonist program. We also hosted product theaters and innovation sessions to highlight our pipeline's differentiation and met with key opinion leaders across the different indications we are pursuing. Among the presentations at Endo was an update of CRN12755, our TSH receptor antagonist candidate for the treatment of Graves’ disease. We believe this novel mechanism of action has the potential to be a single oral therapy that addresses the core driver of Graves’ disease in order to treat both Graves’ hyperthyroidism and treat or prevent thyroid eye disease.

Turning back to the launch of Pellicetti, I'm energized by the team we've built, the progress we've made, the strength of our financial position, and the opportunity to really transform the lives of people with acromegaly. With that, let me turn the call over to Isabel to tell you more.

Speaker 4

Thank you, Scott. Turning to slide four, we are incredibly excited for the anticipated launch of Pellicetti, our recently debuted brand name for Pellicetti. This represents a combination of years of dedicated research and development to bring a newer standard of care to patients with acromegaly. We have made meaningful progress in our interactions with healthcare professionals, patients, and payers as we approach this milestone and complete our transition into a commercial stage company. Moving on to slide five, as Scott mentioned, Crinetics Pharmaceuticals has a significant presence at several prestigious medical meetings over the last few months with global key opinion leaders as well as with community endocrinologists. Our presentations at proceedings at the Endo were standing room only, and healthcare professionals were excited to engage with our team to learn more about Pellicetti.

They were impressed with the new data from the open-label Pathfinder 1 extension, which showed that Pellicetti maintained control of both IGF-1 levels and symptoms through 96 weeks. Healthcare professionals were encouraged by this durability since many patients discontinue acromegaly treatment within a few years. They were also excited by the post-hoc analysis that demonstrated that treatment with Pellicetti improved symptom stability over three, six, and nine months' time periods relative to baseline treatments with injectable SRS. This data could present a compelling value proposition to patients, improved both symptom control and ease of use. In addition, healthcare professionals were reassured by the stability of reduction of tumor volumes in patients who had MRI data throughout the OLE period for both Pathfinder 1 and Pathfinder 2.

We believe that these OLE data demonstrating a stable or decrease in tumor volume over a long period will allow healthcare professionals to feel confident that Pellicetti offers tumor control as well as symptom control and disease control. Turning to slide six, with that in mind, we have built out our commercial team and are in the process of onboarding our sales force ahead of launch. We will have approximately 30 sales representatives in the field, supported by additional healthcare professional-facing roles, ensuring comprehensive coverage and support for our target subscriber base. We have been impressed by both the quantity and quality of candidates who have applied for our field roles, and we are confident they represent the top talent in the industry with extensive experience in rare endocrinology and a high degree of motivation to bring Pellicetti to patients. Now on to slide seven.

Our market research suggests that healthcare professionals perceive Pellicetti as the preferred therapy among newly diagnosed patients due to its rapid reduction of IGF-1 levels and its accelerated titration timeframe relative to monthly injectables. We believe there are 500 newly diagnosed patients per year who are candidates for pharmaceutical therapy. In addition, we believe that there are 11,000 currently diagnosed patients who have high unmet needs and are candidates for Pellicetti. We believe many of these patients might be unhappy with the current treatment options and will consider starting or restarting therapy if an effective, safe, and convenient therapy were available. We are estimating patients to demand more from their acromegaly therapy and believe many will want to switch to Pellicetti over time.

97% of patients from our Pathfinder 1 study who were previously on SRS treatment opted to continue on Pellicetti treatment in the OLE study, underscoring the unmet needs for patients currently on injectable SRS. Other patients are on oral therapies like cabergoline that are not indicated for acromegaly, and they might not have effective control of their disease. Patients on oral opioids might be managing cumbersome twice-daily fasting periods. It is clear that even oral therapies leave room for improvement on both biochemical and symptom control, as well as ease of administration. In addition, we share novel data on injectable SRL discontinuation rates during our science and innovation session at Endo. Over a five-year follow-up period, nearly 80% of patients on injectable SRL did not persist with their newly started treatment regimen. Of those, about two-thirds discontinued treatment altogether.

This data suggests that patients are dissatisfied with the current treatment option and highlights the need for expanded treatment options. Low persistence on injectable SRL when either discontinuing, switching, or adding on represents an opportunity for providers and patients to select a therapy like Pellicetti that can better serve patients' needs. These findings highlight the need for expanded treatment options. We hope that Pellicetti can provide a new option for patients who want a safe, effective, and convenient treatment for their acromegaly. Lastly, we believe that there are at least 17,000 undiagnosed patients. Over time, we believe we can help drive diagnosis and treatment for these patients. Moving to slide eight, our commercial strategy is not just based on growing market share in the naive and switched patients.

It's about growing the market itself by bringing in patients who might have discontinued therapy, those that couldn't tolerate injections, and those who are suboptimally treated. Over time, helping undiagnosed patients accelerate their treatment journey. We know that patient activation will be a key driver of potential uptake and have consequently launched our disease state education campaign and patient support hub well in advance. We're very pleased with the early results from this engagement initiative as this multi-channel strategy will be essential. As we approach potential approval, our goal is to increase awareness, educate the community, and ultimately empower patients to advocate for the best possible care. Turning to slide nine, at this stage in our launch preparations, we have had numerous pre-approval meetings with commercial payers.

We're also grateful for our ongoing engagement with CMS regarding Medicare and Medicaid coverage, particularly given all the changes occurring in the healthcare landscape. Payer groups have been receptive to Pellicetti's value proposition, which includes faster disease control, lower treatment burden, symptom control, and improved patient adherence. We expect that prior authorization activity will closely mirror the label we received for Pellicetti, and we are actively working with payers to ensure appropriate access pathways. Our extensive market research and advisory board feedback have revealed a strong demand among healthcare professionals for a new treatment option. Endocrinologists are eager to use Pellicetti across multiple patient populations: treatment naive patients, those currently on therapy, and importantly, some patients who have been lost to follow up due to the burden of current injectable therapies.

Based on our data and the feedback from healthcare professionals, patients, and payers, we are more confident than ever in the long-term potential for Pellicetti to become the preferred treatment for the acromegaly community. Our commercial strategy is pampered in delivering on that promise. We are deeply enthusiastic about the potential of Pellicetti. I want to offer a few reminders on the expected cadence of launch. In the near term, there are several factors that will affect uptake after potential approval. First, we anticipate formulary placement will take at least six to nine months after launch, which is consistent with other specialty pharmaceutical launches. Second, acromegaly patients see their endocrinologists relatively infrequently, approximately two to four times per year. Consequently, we do not expect a volume of patients on drugs shortly after approval and instead expect adoption of congratulatory rounds in line with our outreach and engagement initiative.

We are all hard at work preparing for U.S. launch, and we continue to progress in our international expansion in anticipation of launching in Europe in 2026. With that, I will turn it over to Dana to provide regulatory and clinical updates. Dana.

Speaker 6

Thanks, Isabel. Turning to slide 10, I'm pleased to provide an update on our regulatory progress across our pipeline, which continues to gain momentum on multiple fronts. Starting with Pellicetti and acromegaly, our ongoing FDA review is progressing as expected through the review milestones, reinforcing our confidence as we approach our September 25th PDUFA date. I'm particularly encouraged that the team we've been working with at FDA hasn't changed, which ensures important continuity throughout this critical review period. Our interactions with the European regulatory authorities also remain on track. Our medical affairs team continues to work in the field, educating HCPs about acromegaly and sharing the data we presented at ACE, IPC, and Endo. These conferences are an opportunity to highlight our clinical results as well as our health economics and outcomes research.

These presentations and resulting publications, much of which are derived from our clinical studies, are part of a broader strategic plan to generate and disseminate evidence of the unmet need in acromegaly and the role Pellicetti could play. Turning to Pellicetti and carcinoid syndrome, we're making steady progress with our phase three program, currently having multiple sites up and running, and continue to expect to enroll the first patient later this year. We are also making significant progress on ethumelonint in CAH, which I will address in more detail shortly. We are revising our timeline for ACTH-dependent Cushing's syndrome as we discuss with regulatory agencies how to best measure effective control given ethumelonint's novel mechanism of action. Moving to our earlier stage pipeline, we presented data on our TSH receptor antagonist candidate at Endo.

The data suggests it has the potential to be a once-daily oral therapy that treats Graves' disease, including both manifestations: Graves' hyperthyroidism and Graves' orbitopathy, also known as thyroid eye disease or TED. Our mechanism of action has the potential to avoid the risks associated with ATVs in anti-IGF-1 therapy, including liver injury, as well as hearing impairment and hyperglycemia. Lastly, we continue to work towards an IND submission for TSH and SST3 this year and for PTH in 2026. Turning to slide 11, for ethumelonint, we've achieved several important milestones in our CAH development program. As a reminder, we shared data on the first three cohorts of our phase two study in January with a primary endpoint of reduction in androstenedione, or A4.

We added a fourth cohort earlier this year, primarily to assess the effect of morning dosing of 80 milligrams of ethumelonint and to study reduction of supraphysiologic glucocorticoid doses in addition to a reduction in A4. Cohort four is now fully enrolled with 10 patients, and so far it continues to support the favorable benefit-risk profile we've observed in our clinical trials to date. We will, of course, continue to monitor these patients very closely and communicate anything necessary in a timely manner. We intend to share the full data from cohort four in early 2026. We also presented data at Endo from the phase two study in CAH, including the full results from the first three cohorts, additional detail on observed reductions in adrenal volume, and reductions in novel biomarkers.

Through these presentations, we continue to demonstrate our advancement of the understanding of the disease biology of CAH, as exemplified by our data on the under-recognized role of 11-oxygenated androgens in CAH. We continue to expect to enroll our first participant in the phase three trial in adult CAH by the end of this year. Additionally, our open-label extension study is actively enrolling, providing continued treatment access for patients. Moving to slide 12, we are also making progress on our registrational trial for ethumelonint in pediatric CAH. When we debuted our phase three adult design last quarter, we outlined our ambition to assess normalization of both androgens and glucocorticoids, and we hope to achieve the same with our operationally seamless phase two-three design for pediatric patients. I am pleased to share with you the pediatric design. The study will consist of three parts.

Part A is the phase two, which is an open-label dose-finding eight-week study that will evaluate safety, efficacy, and reduction of A4 and PKPD. Part B is the phase three, which will be a double-blind placebo-controlled study that will assess safety and efficacy, including the ability to taper GCs. Part C is the open-label extension study for parts A and B, wherein patients from part A will also have the opportunity to taper GCs. We believe our clinical trials are designed to demonstrate differentiation of ethumelonint with an uncompromising endpoint and the goal of developing a new standard of care for patients with CAH. Overall, I am pleased with the significant progress we have made across our early and late-stage programs, and we look forward to providing future updates on each. With that, I will hand the call to Hervé to provide a financial update. Hervé?

Speaker 9

Thank you, Dana. Turning to slide 13, I'm pleased to review our financial results for the second quarter of 2025, which reflect our continued disciplined execution and strategic investment in advancing our pipeline and commercial capabilities. For the second quarter, we recognized $1 million in revenue from our licensing and supply agreements with our Japanese partner, SKK. Our research and development expenses for the second quarter were $80.3 million, compared to $76.2 million in the first quarter. This increase reflects our continued investment in pursuing multiple clinical programs, including progression of Pellicetti for carcinoid syndrome, ethumelonint through late-stage development, and advancement of our novel non-peptide drug conjugate platform into first-in-human studies. Selling, general, and administrative expenses were $49.8 million for the second quarter, compared to $35.5 million in the first quarter.

This increase primarily reflects our strategic investment in building commercial capabilities, including our field sales force and our broader corporate infrastructure as we prepare for Pellicetti's launch. We used $77.8 million of cash on a net basis during the quarter, reflecting continued clinical development and launch preparation activities. We ended the quarter with $1.2 billion in cash, cash equivalents, and investments. As of July 29, 2025, we had approximately 94.2 million shares of common stock outstanding. On a fully diluted basis, we had 111.9 million shares outstanding. Moving to slide 14, looking ahead, we are lowering the high end of our guidance for net cash used in operations in 2025 and now expect to use between $340 million to $370 million, compared to our previous guidance of $340 million to $380 million. This guidance reflects greater precision on clinical timeline estimates and prudent measures we have taken on overhead growth.

We expect net cash used in operations in the second half of the year to be higher than the first half of the year as our late-stage trials gather momentum and our commercialization activities accelerate into an anticipated approval. Based on our current operating plans and cash position, we maintain our guidance that our existing cash and investments will be sufficient to fund our operations into 2029. This provides us with significant runway to execute on multiple value-creating milestones, including the Pellicetti U.S. launch and the advancement of our broader pipeline. With that financial overview, I'll now turn the call back to Scott for some closing remarks.

Speaker 2

Thank you, Toby. Now turning to slide 15, I want to emphasize the strong execution we're demonstrating across all aspects of our business. Our NDA for Pellicetti remains on track with continued collaborative engagement with the FDA. I remain very confident about our launch readiness, supported by the outstanding team we've assembled and our comprehensive corporate readiness for the upcoming launch. We expect multiple phase three and earlier stage readouts across various programs up and down our pipeline over the next several years. We look forward to providing updates as the pipeline continues to mature. As we move through 2025, I'm excited about the opportunity ahead of us to introduce a potential new standard of care for acromegaly patients. We are well positioned to achieve multiple value-creating milestones that will transform Crinetics Pharmaceuticals into the premier endocrine-focused global pharmaceutical company. Thank you all for your continued support.

With that, I'll hand the call back to the operator to begin the Q&A. Please limit yourselves to one question, one question only, in the interest of time. Operator?

Speaker 7

Thank you very much. With that, to start the Q&A, if you'd like to ask a question, please press star followed by one on your telephone keypad. To move yourself in line of questioning, please press star followed by two. Our first question comes from Joseph Patrick Schwartz from Leerink Partners. Joe, your line is now open.

Great, thanks so much, and congrats on all the progress. Neurocrine seems to be doing quite well with the Chronicity launch. I was just wondering, how does that figure into your thinking about the pace of enrollment for your phase three CAH studies now, if at all? Are there any particular kinds of patients who are more likely to go on to Chronicity commercial, versus enroll in a clinical study for ethumelonint? Does that select for any kinds of patients in your view?

Speaker 2

Hi, Joe. Thanks for the question. I think that the launch from Neurocrine is a great thing for patients with CAH, and the momentum of that launch shows some of the unmet need that's out there. In terms of impact on our enrollment in our phase three, either adult or pediatrics, actually, I think it's a positive. In general, it's raising awareness on multiple fronts of the disease. I think that, as another nuance, in general, most of these studies, the bulk of our enrollment has been outside the U.S., not inside the U.S., just because of treatment patterns in the different regions. I think it's all positive for patients. Maybe just ask Dana if she wants to comment on, or Alan, on, kind of the patient population that we're treating.

Speaker 10

Yes, thanks, Scott. I think one interesting difference between their indicated population and what we're trying to achieve in our phase three is that we're looking at a broader patient population because the way we look at it is it's sort of a spectrum. There are patients who have high A4 and high GCs. There are patients that have just high A4 and are not on GCs. Then there's others with normal A4 and high GCs. We think that all of those patients can benefit from ethumelonint. In one sense, it's a much broader population. That is a big distinction and does reflect how we view this particular mechanism of action as addressing the full spectrum of the disease. Thanks for the call.

Speaker 7

Thank you very much. Our next question comes from Tyler Van Buren from TD Cowen. Tyler, your line is now open.

Hi, this is Frances on for Tyler. Could you elaborate on the timeline for the IND submissions of the TSH and SST3 agonists? Are you still targeting 2025?

Speaker 2

Maybe Stephen, you want to give some color on that.

Speaker 0

Yeah, thanks for the question. Those IND enabling work is all still in progress. We are targeting the end of the year. I don't have particular granularity past that, but that's certainly what we're aiming for for both molecules.

Thank you.

Speaker 7

Thank you very much. Our next question comes from Jessica Five from JPMorgan. Jessica, your line is now open.

This is Abdul on for Jess. Can you speak to your comfort level with current consensus numbers for the Pellicetti launch? Thank you.

Speaker 2

Should we all let Tobin take that one?

Speaker 1

Yeah, thanks, Scott. You know, it's not typical for companies at this stage or prudence to comment on, you know, consensus. We haven't given guidance. That's where we are right now. We feel comfortable, though, on the launch preparation and the progress we're making with the FDA. Thank you.

Speaker 7

Thank you very much. As a reminder, if you'd like to raise a question, please signal by pressing star followed by one. Our next question comes from Maxwell School from Morgan Stanley. Maxwell, your line is now open.

Hello, this is Selena on for Max. Thank you for taking our questions. For the global CAH phase three study, what are your expectations around placebo response and any potential impacts from different geographies?

Speaker 2

Dana, or Alan, do you want to comment?

Speaker 10

Yeah, sure. I think that we have a pretty ambitious endpoint as we talk about for the adult trial. We are not really expecting a very high placebo response rate at all. Again, we're setting it up so that you have to sort of address both the A4s and have a reduction in GCs to physiologic levels. In our minds, regardless of which part of the spectrum of CAH you're in, it'll be very difficult for a placebo patient to meaningfully change where they are. That's kind of the way we're looking at it.

Speaker 7

Thank you very much. Our next question comes from Yassine Rahimi from Piper Sandler & Co. Yassine, your line is now open.

Hi team, this is Liam on for Yaz. Just in regard to Pellicetti, we were wondering if you plan to provide color on pricing at the time of approval. Also, with your current payer work, how much do you understand about the level of flexibility you might have to price, when compared to current SST2 injectables?

Speaker 2

Yeah, obviously we'll be discussing price at the right time after what we hope will be an approval soon. Isabel, maybe you want to talk a little bit about the payer side of things.

Speaker 4

Yes, thank you very much for the questions. We have continued to make progress in our discussions with payers, and the value proposition continues to resonate and is very positive. The feedback that we are getting from them, they understand that current treatments, particularly SRLs, have a high burden of treatment, and there is significant waste, with many of the patients, one third of the patients exactly, taking more than 13 injections a year. We continue to partner with them. We continue to reinforce the clinical value of the treatment, and at this time, we are not commenting further on price.

Thank you.

Speaker 7

Thank you very much. Our next question comes from Joshua Elliott Schimmer from Cantor Fitzgerald & Co. Joshua, your line is now open.

Thanks for taking the question. I guess given how much scrutiny there was on the cases of LFT elevation that we're seeing with ethumelonint, can you provide an update on the ongoing experience and whether that's been seen subsequently? How do you plan on kind of maintaining updates going forward on that liver tox profile and whether it is turning into a meaningful signal or the opposite?

Speaker 2

Yeah, thanks, Josh. I think we've said before we're kind of surprised at the scrutiny on that one patient we saw earlier, and we're very comfortable with the emerging and growing experience that we're gaining with it. In terms of updates on it, I think it warrants updates as the data matures and we have something meaningful to share. We should remind everybody that this is part of a much larger program. We're rolling patients into the open-label extension from the phase twos. We're starting to activate sites and we'll be enrolling patients in the adult study and then the pediatric study. I think that kind of emerging experience will give people more and more comfort. If there's a big problem, obviously we'd have to let people know. I think no news is good news on that front.

Thank you.

Speaker 7

Thank you very much. Our next question comes from Alex Thompson from Stifel. Alex, your line is now open.

Speaker 3

Hey guys, this is Chas Schultz on for Alex. We usually have a question about Pellicetti and just how many patients are on the OLE, and how quickly do you expect them to transition to commercial treatment once approved and launched?

Speaker 2

Maybe we'll let, boy, this could be anybody answering this one. I will remind you that we have patients all around the world, not just in the U.S. Maybe Isabel or Dana, you want to comment on that transition?

Speaker 4

Yes, I know we have a little.

Speaker 7

Jana, you're happy to.

Speaker 4

Yeah, go ahead.

Speaker 7

Go ahead, Dr. Dana Pizzuti.

Speaker 2

Sorry.

Speaker 7

Dana, why don't you?

Speaker 2

Go ahead, Isabel.

Speaker 4

I was just going to say, yes, we are okay, sorry about that.

Speaker 10

Okay. The open label extension, as Scott mentioned, is ongoing in numerous countries. With the U.S. approval, there will be, we'll have to see what the outcome of the regulatory interactions are. I think that once the company has reached a PDUFA date and we've had a successful outcome, we can make a decision about what happens with those patients. It's really only a small number of the patients that are in the U.S. that would be potentially enrolled onto commercial drug.

Speaker 3

Got it. Thank you.

Speaker 7

Thank you very much. Our next question comes from Gavin Clark Gartner from Evercore ISI. Gavin, your line is now open.

Hey, this is Yashan for Gavin. Just a quick question from our end. You shared that cohort four of the adult phase two for CAH is going to read out in early 2026. We're wondering if we could also expect any OLE data with this update. Thank you.

Speaker 2

I think this is Scott again. I think we'll have a broader update on the whole program. Remember, in addition to that cohort and the OLE, we should be getting deep into the ramping up of the adult CAH study and the pediatric CAH study. We'll need to provide some clarity on the Cushing's disease program as well. I think there's going to be a ton of things to talk about around ethumelonint in the not-too-distant future.

All right, thank you.

Speaker 7

Thank you very much. Our next question comes from Richard J. Law from Goldman Sachs Group. Rich, your line is now open.

Speaker 8

Hey guys, good afternoon. How much do you think you can learn based on ethumelonint cohort four with only 10 patients? I assume there's going to be data variability. Is there a chance to adjust the phase three protocol based on what you learn in that cohort four since you're starting the phase three study before you see the phase two data? Thanks.

Speaker 2

Yeah, I think that's a good point, a reminder to only 10 patients. We've got quite a few more patients hopefully going into the OLE. Maybe Dana, you want to talk about just the process around protocols?

Speaker 10

As we mentioned, cohort four, one of the interesting questions that we were trying to understand better is the difference between A.M. and P.M. dosing. We've already decided in the phase three that it's going to be P.M. dosing. I think the information for that will be useful afterwards, right, in terms of eventually potentially trying to understand whether patients need that kind of flexibility going forward. We are really locked and loaded for the phase three, as Scott, and you know, we have mentioned before, the sites are already getting started and we expect the first patients in soon. We really aren't planning on making any changes in the protocol right now.

Speaker 7

Thank you very much. As a reminder, if you would like to raise a question, please signal by pressing star followed by one. Our next question comes from Cory Jubinville from LifeSci Capital. Cory, your line is now open.

Good afternoon, and thanks for taking our questions. When we looked at some of the competitive readouts in CAH, the criteria for GC dose reductions were a reflection of maintaining A4 levels within 120% of baseline values. However, that was based on the pre-GC dose A4 levels. When we look to the A4 component in the primary endpoint that you're using for COM and balance studies, that's based off of post-GC dose A4. Obviously, A4 is expected to be lower after a patient takes their morning GC dose. Can you just provide a bit of context as to why specifically you selected post-GC A4 as part of the primary endpoint? How should we be thinking about the clinical relevance of assessing efficacy pre-GC versus post-GC on interesting dye-on? Thanks.

Speaker 2

Yeah, I think that's a great question, Corey. You know, just a reminder that I don't think that keeping A4 levels at 120% of what might be a very high baseline is all that great of a treatment goal for the person dealing with their CAH. We believe they should be getting down to normal or very close to it. Alan, maybe you want to talk about some of those nuances in post and pre-GC dosing. I'll remind you, Corey, that between the primary and the secondary endpoints, we're looking at both. Just as I always encourage everybody, it's the overall profile of the drug that's really important, in addition to the primary endpoint.

Speaker 10

Yeah, it is true that when you administer glucocorticoid, you would expect in this patient population for the A4 level to go down. That is what the regulatory precedent that was set in the Chronicity trials established. That is the optimal time to measure A4 with respect to looking at the trough level of androgen exposure, with the treatment regimen to include the drug plus the glucocorticoids. We use that partly because it's a precedent, but also because it helps to facilitate variability assumptions for sample size calculations. With those assumptions, we know we have a very well-powered trial here at phase three.

That's helpful. Thank you.

Speaker 7

Thank you very much. Our next question comes from Brian Skorney from Baird. Brian, your line is now open.

Hey guys, this is Charlie on for Brian. Thanks for taking the question. We just wanted to dig in a little bit into what you anticipate the distribution looking like, and along those lines, if you anticipate Pellicetti getting captured in data services like IQVIA, for example.

Thanks. Isabel, you want to respond?

Speaker 4

Sorry, I couldn't hear the question well.

Sorry. Give me one second. I was wondering just what you anticipate distribution looking like for Pellicetti, and if you anticipated getting captured in data services like IQVIA, for example.

Yes, thanks for the question. Yes, we have created our distribution system, and it's going to be a closed distribution system at this point. We are not planning to make that data available. It will be blocked. We want to make sure that we are able to track the launch and see, you know, the uptake in different segments. That is not going to be widely available.

Speaker 7

That's helpful. Thank you. Thank you very much. Our next question comes from John Woben from Citizens. John, your line is now open.

Hi, this is Catherine on for John. I just have a quick question about Cushing's disease. If you could provide a little bit more color on discussions on what potential endpoints you're looking at and how the endpoint would differ for your mechanism versus some of the other drugs that have been approved in the indication. Thank you.

Alan, you want to take that?

Speaker 10

Yeah, the primary endpoint for Cushing's disease trials generally is normalization of 24-hour urine-free cortisol excretion. This is a measure of integrated cortisol exposure over a 24-hour period of time, and approvals are usually based on the proportion of patients who achieve normal urine-free cortisol. I mean, I think ethumelonint is uniquely situated here in several ways. One is, in our trials to date, we're running a single center trial at the NIH, and we will be starting larger trials soon. What we're seeing so far is a very rapid normalization of urine-free cortisol in pretty much all the patients tested so far. The rapidity, I think, is unprecedented. The treatment duration at the NIH is 10 days. I mean, within less than 10 days, we are seeing normalization of urine-free.

I'm very excited to expand these trials, to increase the duration of treatment and to enroll more patients to hopefully see this as a consistent finding. If so, I think we have kind of a real new level of treatment for Cushing's disease here.

Speaker 7

Thank you very much. Our next question comes from Andy Chen from Wolfe Research. Andy, your line is now open.

Hey, Brandon on for Andy. You stated earlier that acromegaly patients see endos two to four times a year, which could lead to a slower start to the launch. Shouldn't this approval draw patients to see their docs regardless of their cadence throughout the year? Further, when do you expect patients to start flowing in? Thank you.

Speaker 2

Yeah, thanks. I think this is almost something we can answer for ourselves just based on personal experience of, in most healthcare systems, how long it takes to get to see a specialist, which is unfortunate, but true. Isabel, maybe you want to comment more specifically on the question.

Speaker 4

Yes, most patients are visiting their doctor every six months or once a year. Of course, we are working actively in our engagement with advocacy and our activities in patient activation, as I mentioned before, to get patients to proactively search for those appointments and move them. We know that will take time, and that's what we are cautious about at the beginning. It will take some regular rhythm of patients going to the providers. Our goal is to accelerate this, but we recognize that will be one of the barriers early on.

Thank you.

Speaker 7

Thank you very much. As a reminder, this first question will be star followed by one. Our next question comes from David Leboitz from Citi. David, your line is now open.

Hi, guys. It's Ross on for David. I guess I had a question on Graves’ disease. It seems like a TSH antagonist or an antagonist is an obvious disease-modifying mechanism, yet other people are pursuing other targets. I guess, why do you think there hasn't been a TSH antagonist successfully developed? What do you guys think you're doing differently now with that in mind?

Speaker 2

This is Scott. I think that this is right in our sweet spot, and you could ask that same question about almost any of our earlier, you know, of our programs. These are very difficult targets to address. We've built a capability for this over now 18, no, 17 years at Crinetics. Steve, maybe you want to comment a little bit on what it's taken us to manage to crack this one as well as some of the other programs.

Speaker 0

Yeah, thanks, Scott, and thanks for the question. I do think this is, you know, you look at TSH antagonism for the treatment of Graves’ and the treatment of thyroid eye disease. You know that from a mechanistic standpoint, blocking the action of the receptor is the right thing to do if you can make the right molecule. I think this is, I think as Scott said, this is what we do, you know, for CAH and for Cushing’s. The right thing to do is block the action of the ACTH receptor. The right thing for hyperparathyroidism is to block it at the PTH receptor. Rather than find kind of an end around to try and get an effect, we work to find the right molecules at the right receptors that'll produce the right pharmacology that these patients need.

We have everything from the medicinal chemistry skills and the drug development skills and the understanding of biology and receptor pharmacology to kind of put all those pieces together to find the right molecules.

Thank you.

Speaker 7

Thank you very much. Our next question comes from Douglas Tsao from H.C. Wainwright & Co. Douglas, your line is now open.

Speaker 11

Hi, good afternoon. Thanks for taking the question, and congrats on the progress. I'm just curious, in terms of the balanced CAH study, in terms of part B for the GC tapering, will that replicate what we see or the same protocol that will be used in COM CAH? I believe there's sort of glucocorticoid GC reduction periods followed by sort of GC stable periods, and I think it takes place over two periods. Is that what you're going to be doing in the balanced CAH study as well? Thank you.

Speaker 7

Yeah, Dana or Alan, do you want to take that on study design?

Speaker 10

Yeah, thanks. I think what you were asking, Douglas, about the pediatric phase three part, right? What we're trying to do, it's not exactly the same, but we're trying to demonstrate both efficacy at reduction in A4 and getting GCs tapered, right? I think in the pediatric space, you're always a little bit more cautious with the kids. We have a little bit more flexibility in terms of how the GC reductions take place. I think that is kind of going to be a little bit reflected in the mechanisms of how the investigators carefully titrate them down. What we're looking for is to get patients to normal A4 and then keep trying to titrate them down.

Speaker 11

Is it set in the protocol for investigators to titrate down, or is that investigator discretion?

Speaker 10

The objective of the protocol is to get them to reduce the GCs as much as they can.

Speaker 11

There is no time when they have to achieve it by, or, you know, by 25 weeks or something of that nature or that order.

Speaker 10

Yeah, there is an endpoint to the trial, and so they're expected to be on stable GCs for a four-week period before the end of the trial.

Speaker 11

Okay, great. Thank you for explaining that.

Speaker 10

Twenty-eight weeks. From twenty-four to twenty-eight weeks, it's stable.

Speaker 11

Okay, great. Thank you.

Speaker 7

Thank you very much. Our next question comes from Rohan Mathur from Oppenheimer & Co. Inc. Rohan, your line is now open.

Hey, this is Rohan on for Leland. Thanks for taking my question. On ethumelonint, you've given the timelines for the adult and pediatric trials. How does Crinetics plan to manage the progression towards NDA submission and labeling discussions on incorporating both those, the data from both of those studies down the line? Thanks.

Dana, you want to take that one?

Speaker 10

Thank you for the question. The way that we look at it is, we're looking at each one of those as a distinct submission. I don't think that we'll necessarily hold one until the other one gets done. Whatever gets done first, which, you know, the phase three for the adults is definitely almost begun in phase three, so that should be done before the pediatric one. The way that we look at it is we will submit that. Hopefully, it'll be successful, and then we'll do an amendment or a supplement to add the pediatrics to.

Got it. Thank you.

Speaker 7

Thank you very much. Our next question comes from Catherine Clare Novack from Jones. Catherine, your line is now open.

Hey, good afternoon, guys. Thanks for taking my question. I'm just curious on your thoughts on Pellicetti in surgically naive patients based on the AAC presentation. Is there a market here? Is there a significant number of patients who do forego surgical resection?

Speaker 2

Thanks, Catherine. Let me let Isabel answer that one.

Speaker 4

Thank you. As you know, we have labeled that, and we'll, you know, based on Pellicetti one or Pellicetti two, pending the FDA review. Look at naive and also Cushing's patients. When it comes to presurgical patients, we are very excited about the data that we were able to present at Endo. We also believe that there is an unmet need, but at this time, we are not actively considering that segment. We believe that if physicians see that there is an opportunity and, pending our label, that might be an opportunity in the future.

Okay. Got it. Thanks.

Speaker 7

Thank you very much. That was our final question, and that concludes today's call. We'd like to thank everyone for joining. You may disconnect your lines.